Project Summary/Abstract Glaucoma is a chronic degeneration of the retina and optic nerve, and a leading cause of irreversible blindness, estimated to afflict 80 million people worldwide. It is also the most common neurodegenerative disease in the world, affecting ~3 million Americans with an estimated $2.9 billion annual burden to the US Health Care system. Our understanding of the etiology and molecular mechanisms that drive the pathogenesis of glaucoma remain incomplete. Primary treatment options are limited to lowering intraocular pressure (IOP). There are no neuroprotective therapies to prevent or rescue the degenerative cascades that define glaucoma. Astrocytes are a central driver of structural and parainflammatory changes at the optic nerve head (ONH) and subsequent, irreversible retinal ganglion cells (RGC) death. Emerging evidence indicates that astrocytes have neuroprotective and pro-survival activities in glaucoma. The nature and relevance of these protective signals remains unclear. We recently identified a secreted neuroprotective activity in resting retinal astrocytes, which proved to be a previously unknown resident retinal lipoxin lipid mediator circuit. Lipoxins are a family of potent specialized proresolving lipid mediators (SPMs), which are being developed as drug targets due to their established role in dampening and resolving local inflammation in other tissues. We discovered that two lipoxins, LXA4 and LXB4, are generated by resting astrocytes and in the healthy retina and OHN and that a lipoxin receptor is selectively expressed in RGCs, which identified a previously unknown direct neural activity of lipoxins. This intrinsic pathway is dysregulated in response to retinal/ONH stress. More importantly, we established that therapeutic treatment with lipoxins is neuroprotective by increasing RGC survival and rescuing RGC function in both an acute neurotoxic retinal injury model, and a chronic IOP dependent model of glaucoma like neurodegeneration. We hypothesize that the lipoxin circuit is an important paracrine signaling mechanism to maintain neuronal homeostasis and protect the retina against stress. In a multiple-PI Research Project, we will characterize this novel neuroprotective network, define its mechanism of action and explore the efficacy of amplifying the lipoxin circuit as a therapeutic target for neuroprotection with the following three specific aims: 1) Characterize the mechanism of LXA4 and LXB4 formation in retina, ON, and astrocytes in the context of health and glaucomatous injury, 2) Define the distinct mechanisms of action for LXA4 and LXB4 pro- survival signaling in RGCs, and 3) Investigate the therapeutic potential of amplifying lipoxin circuits to prevent and/or stop RGC degeneration. This goal of this project is to generate transformative insights into a novel neuronal support mechanism and its dysregulation following injury or stress. Most importantly, we will test if amplification of this protective circuit can prevent or stop retinal/optic nerve degeneration and vision loss.